Synthesis of highly-functionalised pyridines via hetero-Diels-Alder methodology: reaction of 3-siloxy-1-aza-1,3-butadienes with electron deficient acetylenes

Article abstract of DOI:10.1016/j.tet.2006.03.051

The hetero-Diels-Alder reaction between 1-aza-3-siloxy-1,3-butadienes and electron deficient acetylenes is described. The reactivity of a range of α,β-unsaturated oximes and hydrazones is assessed in the synthesis of tri- and tetra-substituted pyridines b

Full text of DOI:10.1016/j.tet.2006.03.051

Tetrahedron 62 (2006) 5454–5463
Synthesis of highly-functionalised pyridines via hetero-Diels–
Alder methodology: reaction of 3-siloxy-1-aza-1,3-butadienes
with electron deficient acetylenes
Matthew D. Fletcher,a,b Timothy E. Hurst,b,c Timothy J. Milesd and Christopher J. Moodyb,c,
*
aDepartment of Chemistry, University of Wales Bangor, Bangor, Gwynedd LL57 2UW, UK
bDepartment of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
cSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
dGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 26 January 2006; revised 24 February 2006; accepted 16 March 2006
Available online 12 April 2006
Abstract—The hetero-Diels–Alder reaction between 1-aza-3-siloxy-1,3-butadienes and electron deficient acetylenes is described. The reac-
tivity of a range of a,b-unsaturated oximes and hydrazones is assessed in the synthesis of tri- and tetra-substituted pyridines bearing an oxygen
functionality at C-3. Microwave irradiation has been employed to decrease the extended reaction times and increase the poor yields often
associated with this reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
OMe
N
Me
Me
Me
HN
N
O
OH
The pyridine ring appears in a range of bioactive com-
pounds, both naturally occurring and synthetic, often in
highly substituted form; examples include the lycopodium
alkaloids such as lycodine,1 and the well-known proton-
pump inhibitor omeprazole. Our own particular interest
lies in the thiopeptide antibiotics, a class of sulfur containing
highly modified cyclic peptides characterised by the pres-
ence of a heterocyclic centrepiece consisting of a tri- or
tetra-substituted pyridine embedded in a macrocyclic array.2
Examples of these types of natural products are amythiami-
cin D,3 recently synthesised in our laboratory,4 and nosihep-
tide.5 In our synthesis of amythiamicin D, the pyridine core
was successfully constructed via a biomimetic hetero-Diels–
Alder reaction of a 2-azabutadiene. However, the presence
of a hydroxyl group at C-3 (or C-5) of the pyridine ring, as
in nosiheptide, presents a different challenge.6 Therefore,
as part of our ongoing work towards the synthesis of nosi-
heptide, we decided to investigate a complementary cyclo-
addition route to highly-functionalised pyridines, namely
the hetero-Diels–Alder reaction of 1-aza-3-siloxy-1,3-buta-
dienes with acetylenes.
S
N
S
N
H
O
N
HN
N
OMe
N
S
S
lycodine
omeprazole
pyridine core of
nosiheptide
Since the discovery by Ghosez and co-workers that N,N-
dimethylhydrazones 1, readily available from condensation
of a,b-unsaturated aldehydes and N,N-dimethylhydrazine,
participate readily in [4+2] cycloadditions,7 the hetero-
Diels–Alder reaction of 1-azabutadienes has proved to be a
versatile method for the preparation of a large range of
pyridines and dihydropyridines.8–16 The high reactivity of
these dienes towards electron deficient dienophiles has been
attributed to the strong electron-donating effect of the
dimethylamino substituent. Introduction of an additional
electron-releasing substituent such as an alkyl (1a) or siloxy
(1b) group into the C-3 position was also found to be bene-
ficial.9 In contrast, hetero-Diels–Alder reaction of analogous
a,b-unsaturated oximes 2 have received relatively little
attention in the literature.17–23
R1
R2
R1O
R2
N
NMe2
N
OR3
Keywords: Hetero-Diels–Alder reaction; Pyridines; Microwave irradiation.
* Corresponding author. Tel.: +44 115 846 8500; fax: +44 115 951 3564;
e-mail: c.j.moody@nottingham.ac.uk
1a, R1 = alkyl
2
1b, R1 = OSiR3
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.051

M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
5455
R2
O
TMSO
R1
The scope of the hetero-Diels–Alder reaction of 1-azabuta-
dienes has been extended by the discovery of Boger and
Blagg that N-sulfonyl-2-(ethoxycarbonyl)-1-aza-1,3-buta-
dienes participate in the [4+2] cycloadditions with electron
rich dienophiles.24 Fowler and co-workers have demon-
strated that N-acyl-2-cyano-1-aza-1,3-butadienes may also
be used.25,26 In both cases cycloaddition takes place with
inverse electron demand, in contrast to the hydrazones,
which are considered as ‘normal’ electron rich dienes.
HO
R1
R2
R3
a
b
R1
N
OH
N
N
R3
OTMS
9a-d, 10-12
3a-d
4a-d
5-8
Scheme 1. a: R1¼Me, R2¼R3¼CO2Me; b: R1¼R2¼R3¼CO2Me;
t
c: R1¼CO2 Bu, R2¼R3¼CO2Me; d: R1¼CO2Bn, R2¼R3¼CO2Me; re-
agents and conditions: (a) TMSCl, Et3N, NaI, MeCN, rt, 18 h; (b) benzene
or toluene, reflux, 4–14 days.
Herein we report our findings on the synthesis of highly-
functionalised pyridines from 3-siloxy-1-aza-1,3-butadienes
and electron deficient acetylenes. In particular, application
of microwave irradiation has been investigated to decrease
the relatively long reaction times commonly observed under
standard thermal conditions. In accordance with Ghosez’s
initial observations, electron-donating substituents on nitro-
gen were found to accelerate the rate of cycloaddition.9 Less
electron rich dienes may also be employed, although higher
temperatures and longer reaction times are often necessary.
Table 1. Cycloaddition of a,b-unsaturated oximes with acetylenes under
thermal conditions
Entry R1
R2
R3
Product Time
(days)
Yield (%)a
1
2
3
4
Me CO2Me CO2Me 9a
CO2Me CO2Me CO2Me 9b
4
4
14
6
7
4
0.8
38
42
39
48
32
21
39
t
CO2 Bu CO2Me CO2Me 9c
CO2Bn CO2Me CO2Me 9d
CO2Me CO2Me CO2 Bu 10
t
5
6b
7c
CO2Bn
CO2Me
H
H
CO2Me 11
COMe 12
a
b
c
Isolated yield after chromatography on silica.
Methyl propiolate (2 equiv), toluene, sealed tube and 120 ꢀC.
3-Butyn-2-one (5 equiv), toluene, sealed tube and 110 ꢀC.
2. Results and discussion
2.1. Synthesis and cycloadditions of a,b-unsaturated
oximes
microwave irradiation of 1-azadiene 4b with DMAD (5) in
toluene in a sealed vessel at 150 ꢀC afforded only degrada-
tion products. A more hydrolytically stable silyl protecting
group was therefore investigated; we chose the bulkier
tert-butyldimethylsilyl (TBDMS) derivatives 13a and 13b,
prepared from the free oximes 3a and 3b, respectively, using
A range of 3-siloxy-1-azadienes 4a–d was prepared from the
corresponding free oximes 3a–d27–28 according to known or
modified procedures,17 and their reactivity in the hetero-
Diels–Alder reaction was evaluated (Scheme 1). Furukawa
and co-workers have reported that the cycloaddition of
1-azadiene 4a and methyl ester 4b with dimethyl acetylene-
dicarboxylate (DMAD, 5) proceeds in 60% and 62% yield,
respectively, after heating under reflux in benzene for
8 h.17 However, attempts to repeat these results in our labo-
ratory proved less successful, with the 3-hydroxypyridines
9a and 9b isolated in 38% and 42% yield, respectively,
only after heating under reflux in benzene for several days
(Table 1, entries 1 and 2). The trimethylsilyl group is pre-
sumably lost on work-up. Similar results were obtained on
reaction of ester analogues 4c and 4d with DMAD (5) in
refluxing toluene (Table 1, entries 3 and 4). Poor yields
may be explained by the recovery of a large amount (up to
45%) of an O-trimethylsilyl keto-oxime side-product due
to silyl enol ether hydrolysis under these conditions. As
may be expected, changing the dienophile for the bulkier
di-tert-butyl acetylenedicarboxylate (6) increases the reac-
tion time and lowers the yield (Table 1, entry 5). Moderate
yields were also obtained from the less reactive unsymmet-
rical dienophiles methyl propiolate (7, Table 1, entry 6) and
3-butyn-2-one (8, Table 1, entry 7). A single regioisomer was
obtained in both cases, the regiochemistry being that
expected on the basis of the likely coefficients of the relevant
frontier orbitals (HOMOdiene/LUMOdienophile).
TBDMS triflate and Hunigs base (Scheme 2). Treatment of
¨
13a and 13b with either 1 or 2 equiv of DMAD (5) in a sealed
tube at 150 ꢀC under microwave irradiation (300 W) pro-
ceeded smoothly to afford the protected pyridines in moder-
ate yields after only a few hours (Table 2, entries 1, 3 and 5).
Increasing the temperature to 180 ꢀC shortens the reaction
time even further (Table 2, entries 2, 4, 6 and 7). A control
O
R
TBDMSO
R
TBDMSO
R
CO2Me
CO2Me
a
b
N
OH
N
N
OTBDMS
3a-b
13a-b
14a-b
Scheme 2. a: R¼Me; b: R¼CO2Me; reagents and conditions: (a)
TBDMSOTf, EtiPr2N, CH2Cl2, 0 ꢀC, 5–18 h; (b) DMAD, toluene or tolu-
ene/THF, MW (300 W).
Table 2. Cycloaddition of a,b-unsaturated oximes with acetylenes under
microwave conditionsa
Entry
R
DMAD Temp (ꢀC) Time (h) Product Yield (%)b
(equiv)
1
2
3
4
5
6
7
Me
Me
Me
Me
CO2Me 2.0
CO2Me 2.0
CO2Me 1.0
2.0
2.0
1.0
1.0
150
180
150
180
150
180
180
6
2
8
3
10
6
14a
14a
14a
14a
14b
14b
14b
56
56
50
50
32
31
45
The application of microwave irradiation has been shown to
accelerate the rate of many organic reactions.29,30 Indeed,
several examples of hetero-Diels–Alder reactions have
been reported under microwave conditions, including both
1- and 2-azadienes.4,31–34 We envisaged that the long
reaction times previously observed might be reduced by per-
forming the reaction under these conditions. Unfortunately,
8
a
Reactions were carried out in a CEM DiscoverÔ microwave reactor
operating at 300 W with simultaneous cooling.
Isolated yield after chromatography on silica.
b

5456
M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
reaction performed in a sealed tube at 150 ꢀC gave the appro-
priate pyridine 14a in 57% yield after 6 h. However, the use
of microwave irradiation remains as a safe, clean and effi-
cient means for performing high temperature reactions and
was used in the following studies on hydrazone derived
1-azadienes.
ether and in poor yield, due to the competing formation
of Michael adducts between the dienophile and liberated
dimethylamine (Table 3, entry 4), a problem commonly
observed with N,N-dimethylhydrazones that is not found
with oximes.14 Thus, 2 equiv of the dienophile were neces-
sary to achieve complete consumption of the 1-azadiene,
allowing the product to be isolated in comparable yield
to the thermal reaction in only 2 h (Table 3, entry 5). Once
again, increasing the temperature to 180 ꢀC shortens the re-
action time (Table 3, entry 6). A control reaction performed
in a sealed tube at 150 ꢀC under thermal conditions gave the
appropriate pyridine 14a in 46% yield after 2 h.
2.2. Synthesis and cycloadditions of a,b-unsaturated
hydrazones
As discussed above, the most commonly used 1-azadienes in
hetero-Diels–Alder reactions are the N,N-dimethylhydra-
zones 1a, and a number of reactions with electron deficient
alkenes and benzoquinones as dienophiles have been re-
ported.15 Reactions with alkynes are less common. The
C-3 oxygenated 1-azadienes, hydrazones 1b, are also
known,9,14,15,35 although to our knowledge, no Diels–Alder
reactions of these dienes with alkynes have been reported.
Hence, our initial work on hydrazones focussed on the cy-
cloaddition of the previously unknown 1-dimethylamino-
2-methyl-3-trimethylsiloxy-1-aza-1,3-butadiene with DMAD
(5). However, only 30% of the desired cycloadduct was ob-
tained after heating under reflux in toluene for 5 days. As has
been shown with the oximes, a more hydrolytically stable di-
ene is obtained by employing the TBDMS derivative. Thus,
treatment of the known35 1-azadiene 17a with DMAD (5)
gave the desired cycloadduct 14a in 53% yield after 20 h
(Table 3, entry 3). Once again we turned our attention to
the use of microwave irradiation in an attempt to decrease
the reaction time and improve the yield.
1-Azadienes 15 and 16 were prepared from butane-2,3-dione
monohydrazone35 via analogous procedures to the oximes in
order to evaluate the effect of different silyl protecting
groups on diene reactivity. Cycloaddition of triethylsilyl
(TES) analogue 15 with DMAD (5) gave, after acidic
work-up, the deprotected pyridine 9a in 34% yield (Table
3, entry 1). The tert-butyldiphenylsilyl (TBDPS) analogue
16 however, could not be induced to undergo cycloaddition,
even at elevated temperatures (Table 3, entry 2). This con-
firmed our choice of the TBDMS ether 17a as the most suit-
able 3-siloxy-1-azadiene.
To date, the only comparative study on the effect of the N-1
nitrogen substituents of hydrazones on 1-azadiene reactivity
has been reported by Gilchrist and co-workers.36,37 There-
fore, we prepared the 1-aza-1,3-butadienes 17b–d from
2,3-butanedione in two steps by condensation with the ap-
propriate hydrazine and silyl enol ether formation, in order
to probe the effect on diene reactivity and reaction by-prod-
uct profile. As expected, the piperidinyl derivative 17b pos-
sessed similar reactivity to 17a (Table 3, entry 7), including
the formation of unwanted Michael adducts. Introduction of
a single electron withdrawing substituent onto the leaving
group (17c) also failed to prevent by-product formation (Ta-
ble 3, entry 8). However, the introduction of a second elec-
tron withdrawing group in hydrazone 17d, derived from
N-aminophthalimide,38 completely suppressed Michael ad-
dition of the nitrogen leaving group into the dienophile,
leading to increased yield, although higher temperature is
necessary to effect the cyclisation (Table 3, entry 9). Only
a single equivalent of DMAD (5) is needed with this diene
(Table 3, entry 10).
Irradiation of equimolar amounts of 1-azadiene 17a and
DMAD (5) at 150 ꢀC in toluene in a sealed tube for 2 h
afforded the desired pyridine, still protected as the TBDMS
R2
R1O
Me
R1O
Me
R2
R3
a
N
X
N
R3
15-16, 17a-d
5, 7-8
14a, 18-19
Scheme 3. a: X¼NMe2, R2¼R3¼CO2Me; b: X¼piperidinyl,
R2¼R3¼CO2Me; c: X¼NMeCbz, R2¼R3¼CO2Me; d: X¼phthalimido,
R2¼R3¼CO2Me; reagents and conditions: (a) toluene or toluene/THF,
MW (300 W).
Table 3. Cycloaddition of a,b-unsaturated hydrazones with acetylenes under microwave conditions,a using 2 equiv of dienophile
Entry
1-Azadiene
R1
R2
R3
Temp (ꢀC)
Time (h)
Product
Yield (%)b
1
15
16
TES
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
150
180
110
150
150
180
150
150
180
180
180
180
2
6
20
2
2
0.75
2
4
3
4
6
9a
—
34
—
53
24
52
44
47
46
58
54
29
28
2
TBDPS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
3c
4d
5
17a
17a
17a
17a
17b
17c
17d
17d
17a
17a
14a
14a
14a
14a
14a
14a
14a
14a
18
6
7
8
9
10d
11
12
H
6
19
a
Reactions were carried out in a CEM DiscoverÔ microwave reactor operating at 300 W with simultaneous cooling.
Isolated yield after chromatography on silica.
Reaction carried out under thermal conditions in refluxing toluene.
DMAD (1 equiv).
b
c
d

M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
5457
Unsymmetrical dienophiles 7 and 8 were also investigated.
The most reactive 1-azadiene 17a was chosen for this study
as longer reaction times were expected with the less electron
deficient (and hence less reactive) dienophiles. Indeed, in-
creasing the reaction temperature to 180 ꢀC for 6 h was nec-
essary to achieve complete consumption of the diene. Poor
yields of a single regioisomer were obtained, in an analogous
fashion to the oximes (Table 3, entries 11and 12; Scheme 3).
The mixture was stirred at room temperature overnight and
then the solvent was removed in vacuo. Ether (60 mL) was
added to the residue, which was then filtered. The filtrate
was concentrated in vacuo and distilled (Kugelrohr) to afford
the title compound.
4.2. General procedure 2 for the silylation of a-keto-
oximes
To a stirred solution of the a-keto-oxime (5.0 mmol) in dry
dichloromethane (10 mL) at 0 ꢀC was added dropwise ethyl-
diisopropylamine (1.68 g, 13.0 mmol) and tert-butyldi-
methylsilyl trifluoromethanesulfonate (3.30 g, 12.5 mmol).
Stirring was continued at 0 ꢀC for 2–4 h and then the solvent
was evaporated. The residue was diluted with n-pentane
(25 mL), stirred at 0 ꢀC for 1 h, then filtered and evaporated
to afford the title compound, which was used without further
purification.
3. Conclusions
The hetero-Diels–Alder reaction between 1-aza-3-siloxy-
1,3-butadienes and electron deficient acetylenes has been
investigated. We have expanded the scope of 3-siloxy-a,b-
unsaturated oximes as heterodienes, and utilised microwave
irradiation to reduce the often extended reaction times and
improve the poor yields associated with this process.
4.3. General procedure 3 for the preparation of a-keto-
hydrazones
A series of 3-siloxy-a,b-unsaturated hydrazones were also
prepared and their reactivity in the hetero-Diels–Alder reac-
tion was evaluated. More electron rich 1-azadienes proved to
be most reactive, although side reactions were observed.
Introduction of electron withdrawing groups into the hydra-
zone suppressed these side reactions, but higher tempera-
tures were required for cycloaddition.
To
a stirred solution of 2,3-butanedione (0.861 g,
10.0 mmol) in ethanol (10 mL) at 0 ꢀC was added the hydra-
zine (11.0 mmol) in dropwise. Stirring was continued at
0 ꢀC until the reaction was judged to be complete by TLC.
The solution was then dried over MgSO4 and concentrated
in vacuo. The crude product was purified by flash chroma-
tography on silica, eluting with ethyl acetate–light petroleum
(1:9) to afford the title compound.
4. Experimental
Commercially available reagents were used throughout
without further purification unless otherwise stated; solvents
were dried by standard procedures. Light petroleum refers to
the fraction with bp 40–60 ꢀC and ether refers to diethyl
ether. Reactions were routinely carried out under a nitrogen
atmosphere. Microwave reactions were carried out in a CEM
DiscoverÔ 300 W focussed microwave reactor. Fully char-
acterised compounds were chromatographically homo-
geneous. IR spectra were recorded in the range 4000–
4.4. General procedure 4 for the silylation of a-keto-
hydrazones
To a stirred solution of the a-ketohydrazone (10.0 mmol) in
dry dichloromethane (10 mL) at 0 ꢀC was added dropwise
ethyldiisopropylamine (1.68 g, 13.0 mmol) and tert-butyl-
dimethylsilyl trifluoromethanesulfonate (3.30 g, 12.5 mmol).
Stirring was continued at 0 ꢀC for 2 h and then the solvent
was evaporated. The residue was diluted with n-pentane
(25 mL), stirred at 0 ꢀC for 1 h, then filtered and evaporated
to afford the title compound, which was used without further
purification.
1
600 cmꢁ1 using a Nicolet Magna FT-550 spectrometer. H
and 13C NMR spectra were recorded at 300 or 400 MHz
(1H frequencies, corresponding 13C frequencies are recorded
at 75 and 100 MHz). In the 13C NMR spectra, signals corre-
sponding to CH, CH2 or CH3 groups are assigned from
DEPT. High and low-resolution mass spectra were recorded
on a Micromass GCT time of flight high-resolution mass
spectrometer, or at the EPSRC Mass Spectrometry Service
(Swansea). Elemental analysis was carried out on a Perkin
Elmer 2400 CHN analyser within ꢂ0.3% of the theoretical
values. Melting points were measured on a Gallenkamp
electrothermal digital melting point apparatus or on a Reich-
ert–Kofler hot stage apparatus. Compounds 3b,27 3c,28 3d,27
N,N-dimethyl butane-2,3-dione monohydrazone35 and 17a35
were prepared according to literature procedure.
4.5. General procedure 5 for hetero-Diels–Alder reac-
tion under thermal conditions
Equimolar amounts of the 1-aza-1,3-butadiene and the
dienophile were heated under reflux in the appropriate sol-
vent (2 mL per mmol of 1-azadiene) for the time indicated.
The resulting mixture was concentrated in vacuo, and the
crude product was purified by flash chromatography on
silica, eluting with methanol–chloroform (0.5:99.5–2:98)
to afford the title compound.
4.6. General procedure 6 for hetero-Diels–Alder reac-
tion under microwave irradiation
4.1. General procedure 1 for the silylation of a-keto-
oximes
A solution of the 1-aza-1,3-butadiene (1.0 mmol) and the
dienophile (1.0–2.0 mmol) in toluene (2 mL) in a sealed mi-
crowave tube (10 mL capacity) was irradiated at 300 W with
simultaneous cooling and held at 150 ꢀC for the time indi-
cated. The resulting mixture was concentrated in vacuo,
To a stirred mixture of the a-keto-oxime (13.5 mmol) and
sodium iodide (2.02 g, 13.5 mmol) in dry acetonitrile
(40 mL) was added dropwise triethylamine (5.46 g,
54.0 mmol) and chlorotrimethylsilane (5.87 g, 54.0 mmol).

5458
M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
and the crude product was purified by flash chromatography
on silica, eluting with ethyl acetate–light petroleum (1:19) to
afford the title compound.
(CH), 128.3 (CH), 101.1 (CH2), 66.9 (CH2), 0.0 (SiMe3),
ꢁ0.8 (SiMe3); m/z (EI) 365 (M+, 1%), 350 (2), 274 (19),
91 (100), 73 (56).
4.7. General procedure 7 for hetero-Diels–Alder reac-
tion under microwave irradiation
4.7.5. 2-Methyl-1,3-bis(tert-butyldimethylsiloxy)-1-aza-
1,3-butadiene 13a. Following general procedure 2, the title
compound (1.44 g, 87%) was obtained as a pale oil from 2,3-
butanedione monoxime (0.435 g, 5.0 mmol); (Found: MH+,
330.2281. C16H35NO2Si2+H requires 330.2284); nmax
(film)/cmꢁ1 2957, 2931, 2888, 2859, 1615, 1580, 1472,
1464, 1391, 1362, 1340, 1254, 1168; dH (300 MHz,
CDCl3) 4.78 (1H, d, J¼1.1 Hz, C]CH), 4.48 (1H, d,
J¼1.1 Hz, C]CH), 1.96 (3H, s, Me), 0.94 (9H, s, CMe3),
0.92 (9H, s, CMe3), 0.16 (6H, s, SiMe2), 0.14 (6H, s,
SiMe2); dC (75 MHz, CDCl3) 158.2 (C), 154.1 (C), 96.6
(CH2), 26.5 (Me), 26.1 (Me), 18.6 (CMe3), 18.4 (CMe3),
11.6 (Me), ꢁ4.1 (SiMe2), ꢁ4.3 (SiMe2); m/z (CI) 358
(15%), 330 (MH+, 90), 314 (100), 272 (85), 231 (37), 216
(13), 200 (18), 189 (30), 156 (12), 115 (21).
A solution of the 1-aza-1,3-butadiene (1.0 mmol) and the
dienophile (1.0–2.0 mmol) in toluene (2 mL) and THF
(0.25 mL) in a sealed microwave tube (10 mL capacity)
was irradiated at 300 W with simultaneous cooling and
held at 180 ꢀC for the time indicated. The resulting mixture
was concentrated in vacuo, and the crude product was
purified by flash chromatography on silica, eluting with
ethyl acetate–light petroleum (1:19) to afford the title
compound.
4.7.1. 2-Methyl-1,3-bis(trimethylsiloxy)-1-aza-1,3-buta-
diene 4a. Following general procedure 1 using similar molar
amounts, the title compound was obtained from 2,3-butane-
dione monoxime in 37% yield as a colourless oil, bp 80–
100 ꢀC (oven temperature) at 3 mmHg; dH (400 MHz,
CDCl3) 4.81 (1H, d, J¼1.4 Hz, C]CH), 4.55 (1H, d,
J¼1.4 Hz, C]CH), 1.96 (3H, s, Me), 0.23 (9H, s, SiMe3),
0.22 (9H, s, SiMe3). This compound has been prepared
previously.17
4.7.6. 2-Methoxycarbonyl-1,3-bis(tert-butyldimethyl-
siloxy)-1-aza-1,3-butadiene 13b. Following general proce-
dure 2, the title compound (1.73 g, 93%) was obtained as
a pale oil from 3b (0.716 g, 5.0 mmol); (Found: MH+,
374.2182. C17H35NO4Si2+H requires 374.2183); nmax
(film)/cmꢁ1 2956, 2931, 2887, 2859, 1751, 1614, 1473,
1464, 1435, 1391, 1362, 1254, 1102; dH (300 MHz,
CDCl3) 4.68 (1H, d, J¼2.1 Hz, C]CH), 4.64 (1H, d,
J¼2.1 Hz, C]CH), 3.83 (3H, s, OMe), 0.94 (9H, s,
CMe3), 0.89 (9H, s, CMe3), 0.16 (12H, s, 2ꢃSiMe2); dC
(75 MHz, CDCl3) 164.3 (C), 155.2 (C), 149.1 (C), 100.3
(CH2), 52.4 (Me), 26.1 (Me), 26.0 (Me), 18.5 (CMe3),
18.3 (CMe3), ꢁ4.3 (SiMe2), ꢁ5.0 (SiMe2); m/z (CI) 402
(8%), 374 (MH+, 32), 358 (50), 316 (60), 286 (10), 247
(18), 231 (90), 200 (10), 189 (100), 184 (20), 157 (40),
147 (50), 115 (70), 86 (100), 73 (28).
4.7.2. 2-Methoxycarbonyl-1,3-bis(trimethylsiloxy)-1-
aza-1,3-butadiene 4b. Following general procedure 1 using
similar molar amounts, the title compound was obtained
from 3b in 85% yield as a colourless oil, bp 130–150 ꢀC
(oven temperature) at 0.3 mmHg; dH (400 MHz, CDCl3)
4.71 (1H, d, J¼2.0 Hz, C]CH), 4.68 (1H, d, J¼2.0 Hz,
C]CH), 3.84 (3H, s, OMe), 0.22 (18H, s, 2ꢃSiMe3). This
compound has been prepared previously.17
4.7.3. 2-tert-Butoxycarbonyl-1,3-bis(trimethylsiloxy)-1-
aza-1,3-butadiene 4c. Following general procedure 1 using
similar molar amounts, the title compound was obtained
from 3c in 82% yield as a colourless oil, bp 140–155 ꢀC
(oven temperature) at 0.3 mmHg; (Found: M+, 331.1636.
C14H29NO4Si2 requires 331.1636); nmax (film)/cmꢁ1 2965,
1740, 1615, 1370, 1255, 1175, 1105, 1025, 965, 845, 755;
dH (400 MHz, CDCl3) 4.72 (1H, d, J¼1.9 Hz, C]CH),
4.70 (1H, d, J¼1.9 Hz, C]CH), 1.53 (9H, s, CMe3), 0.23
(9H, s, SiMe3), 0.22 (9H, s, SiMe3); dC (100 MHz, CDCl3)
162.6 (C), 155.5 (C), 148.6 (C), 100.7 (CH2), 83.0
(CMe3), 28.0 (CMe3), 0.0 (SiMe3), ꢁ0.9 (SiMe3); m/z (EI)
331 (M+, 17%), 275 (17), 274 (10), 259 (10), 147 (27),
115 (16), 113 (25), 75 (44), 74 (20), 73 (81), 57 (100).
4.7.7. 1-(Dimethylamino)-2-methyl-3-(trimethylsiloxy)-
1-aza-1,3-butadiene. To a solution of N,N-dimethyl butane-
2,3-dione monohydrazone (1.60 g, 12.5 mmol) and sodium
iodide (0.934 g, 6.20 mmol) in acetonitrile (30 mL) was
added triethylamine (2.52 g, 25.0 mmol) and chlorotri-
methylsilane (2.71 g, 25.0 mmol). The reaction mixture was
stirred for 18 h. The reaction mixture was then concentrated
in vacuo and the residue was diluted with ether (50 mL), fil-
tered under nitrogen and concentrated in vacuo. The crude
product was distilled to afford the title compound as a brown
oil (1.69 g, 68%), bp 115–130 ꢀC (oven temperature) at
9 mmHg; (Found: M+, 200.1343. C9H20N2OSi requires
200.1345); nmax (film)/cmꢁ1 2990, 2955, 2900, 2860,
2820, 2775, 1685, 1615, 1590, 1470, 1440, 1335, 1280; dH
(300 MHz, CDCl3) 4.85 (1H, d, J¼1.1 Hz, C]CH), 4.81
(1H, d, J¼1.1 Hz, C]CH), 2.54 (6H, s, NMe2), 2.02 (3H,
s, Me), 0.22 (9H, s, SiMe3); dC (75 MHz, CDCl3) 159.5
(C), 155.3 (C), 96.8 (CH2), 47.1 (Me), 14.2 (Me), 0.35
(Me); m/z (EI) 311 (25%), 271 (14), 200 (17), 185 (56),
151 (48), 135 (48), 109 (78), 86 (45), 73 (91), 58 (100).
4.7.4. 2-Benzyloxycarbonyl-1,3-bis(trimethylsiloxy)-1-
aza-1,3-butadiene 4d. Following general procedure 1 using
similar molar amounts, the title compound was obtained
from 3d in 66% yield as a colourless oil, bp 200–225 ꢀC
(oven temperature) at 0.3 mmHg; (Found: M+, 365.1476.
C17H27NO4Si2 requires 365.1479); nmax (film)/cmꢁ1 3035,
2960, 2900, 1750, 1700, 1615, 1500, 1455, 1380, 1350,
1315, 1255, 1100, 1020; dH (300 MHz, CDCl3) 7.42–7.30
(5H, m, ArH), 5.32 (2H, s, CH2), 4.70 (1H, d, J¼2.0 Hz,
C]CH), 4.65 (1H, d, J¼2.0 Hz, C]CH), 0.22 (9H, s,
SiMe3), 0.20 (9H, s, SiMe3); dC (75 MHz, CDCl3) 163.3
(C), 154.4 (C), 148.4 (C), 135.3 (C), 128.5 (CH), 128.3
4.7.8. 1-(Dimethylamino)-2-methyl-3-(triethylsiloxy)-1-
aza-1,3-butadiene 15. To a solution of N,N-dimethyl
butane-2,3-dione monohydrazone (1.28 g, 10.0 mmol) and
sodium iodide (0.750 g, 5.00 mmol) in acetonitrile
(20 mL) was added triethylamine (2.02 g, 20.0 mmol) and

M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
5459
chlorotriethylsilane (3.01 g, 20.0 mmol). The reaction mix-
ture was stirred for 24 h, then further sodium iodide
(0.375 g, 2.50 mmol), triethylamine (1.01 g, 10.0 mmol)
and chlorotriethylsilane (1.50 g, 10.0 mmol) was added,
and the reaction mixture was stirred for further 18 h. The re-
action mixture was then concentrated in vacuo and the resi-
due was diluted with ether (35 mL), filtered under nitrogen
and concentrated in vacuo. The crude product was distilled
in vacuo at room temperature to afford the title compound
as a brown oil (1.62 g, 67%); (Found: M+, 242.1808.
C12H26N2OSi requires 242.1814); nmax (film)/cmꢁ1 3428,
2953, 2821, 2777, 1684, 1611, 1589, 1459, 1415, 1379,
1337, 1238, 1210, 1147; dH (300 MHz, CDCl3) 4.77 (1H,
d, J¼0.8 Hz, C]CH), 4.40 (1H, d, J¼0.8 Hz, C]CH),
2.47 (6H, s, NMe2), 1.97 (3H, s, Me), 0.93 (9H, t,
J¼7.9 Hz, 3ꢃCH2Me), 0.67 (6H, q, J¼7.9 Hz, 3ꢃCH2Me);
dC (75 MHz, CDCl3) 160.2 (C), 155.9 (C), 96.0 (CH2), 47.5
(Me), 14.6 (Me), 7.1 (Si(CH2Me)3), 7.0 (Si(CH2Me)3), 6.8
(Si(CH2Me)3), 5.6 (Si(CH2Me)3); m/z (EI) 242 (M+, 18%),
227 (48), 217 (92), 213 (20), 189 (100), 170 (10), 161
(51), 133 (17), 115 (28), 105 (14), 87 (50), 83 (33), 75
(13), 58 (34).
4.7.11. 3-(tert-Butyldimethylsiloxy)-2-methyl-1-(piperi-
dinyl)-1-aza-1,3-butadiene 17b. Following general proce-
dure 4, the title compound (0.715 g, 84%) was obtained as
a
pale oil from 3-(piperidin-1-ylimino)-butan-2-one
(0.504 g, 3.0 mmol); (Found: MH+, 283.2205. C15H30N2O-
Si+H requires 283.2205); nmax (CHCl3)/cmꢁ1 3386, 2934,
2857, 2817, 1615, 1593, 1472, 1442, 1360, 1334, 1253,
1160, 1036; dH (300 MHz, CDCl3) 4.86 (1H, d, J¼0.9 Hz,
C]CH), 4.52 (1H, d, J¼0.9 Hz, C]CH), 2.75–2.71 (4H,
m, 2ꢃCH2), 2.04 (3H, s, Me), 1.72–1.65 (4H, m, 2ꢃCH2),
1.48–1.44 (2H, m, CH2), 0.96 (9H, s, CMe3), 0.17 (6H, s,
SiMe2); dC (75 MHz, CDCl3) 160.4 (C), 156.2 (C), 96.9
(CH2), 56.5 (CH2), 26.2 (CH2), 25.7 (CH2), 24.3 (CH2),
18.8 (CMe3), 14.8 (Me), ꢁ2.5 (SiMe2); m/z 311 (8%), 283
(MH+, 100), 267 (45), 225 (30), 200 (5), 169 (10), 159 (5).
4.7.12. 1-Benzyloxycarbonyl-1-methyl-hydrazine. To
a stirred solution of methylhydrazine (0.461 g, 10.0 mmol)
in dry dichloromethane (20 mL) at 0 ꢀC was added triethyl-
amine (1.21 g, 12.0 mmol) and benzyl chloroformate
(1.88 g, 11.0 mmol). The reaction was allowed to warm to
room temperature and stirred for 2 h. Water (15 mL) was
added and the organic layer was separated. The aqueous
layer was further extracted with dichloromethane
(3ꢃ25 mL). The combined organics were dried over
MgSO4 and concentrated in vacuo. The crude product was
purified by flash chromatography on silica, eluting with
ethyl acetate–light petroleum (1:1) to afford the title com-
pound as a pale oil (1.04 g, 58%), lit. bp 104–134 ꢀC,
0.2 mmHg; nmax (CHCl3)/cmꢁ1 3026, 3014, 1697, 1627,
1498, 1455, 1395, 1351, 1310, 1230, 1169; dH (300 MHz,
CDCl3) 7.38–7.31 (5H, m, ArH), 5.15 (2H, s, CH2), 3.82
(2H, br s, NH2), 3.14 (3H, s, Me). This compound has
been prepared previously.39
4.7.9. 3-(tert-Butyldiphenylsiloxy)-1-(dimethylamino)-2-
methyl-1-aza-1,3-butadiene 16. To a solution of N,N-
dimethyl butane-2,3-dione monohydrazone (0.256 g,
2.00 mmol) and sodium iodide (0.150 g, 1.00 mmol) in
acetonitrile (2 mL) was added triethylamine (0.405 g,
4.00 mmol) and tert-butyldiphenylsilyl chloride (1.10 g,
4.00 mmol). The reaction mixture was stirred for 3 days,
then further sodium iodide (0.150 g, 1.00 mmol), triethyl-
amine (0.405 g, 4.00 mmol) and tert-butyldiphenylsilyl
chloride (1.10 g, 4.00 mmol) was added and stirring was
continued for further 24 h. The reaction mixture was then
concentrated in vacuo and the residue was diluted with ether
(15 mL), cooled in an ice-bath for 30 min, filtered and con-
centrated in vacuo. The crude product was purified by flash
chromatography on silica to afford the title compound as
a brown oil (0.471 g, 64%); (Found: M+, 366.2124.
C22H30N2OSi requires 366.2127); nmax (CHCl3)/cmꢁ1
3392, 3072, 3050, 2958, 2931, 2892, 2858, 1611, 1590,
1472, 1428, 1336, 1317, 1157, 1114; dH (300 MHz,
CDCl3) 7.76–7.70 (4H, m, ArH), 7.42–7.34 (6H, m, ArH),
4.77 (1H, d, J¼1.5 Hz, C]CH), 4.30 (1H, d, J¼1.5 Hz,
C]CH), 2.35 (6H, s, NMe2), 2.06 (3H, s, Me), 1.05 (9H,
s, CMe3); dC (75 MHz, CDCl3) 159.3 (C), 155.5 (C), 135.9
(CH), 135.4 (CH), 133.9 (C), 128.2 (CH), 96.8 (CH2), 47.3
(NMe2), 27.1 (Me), 20.2 (CMe3), 14.9 (Me); m/z (EI) 366
(M+, 19%), 351 (17), 309 (46), 273 (15), 266 (19), 200
(100), 181 (49), 135 (35), 77 (43).
4.7.13. N-Benzyloxycarbonyl-N-methyl butane-2,3-dione
monohydrazone. Following general procedure 3, the title
compound (0.963 g, 78%) was obtained as a colourless solid
from 1-methyl-1-benzyloxycarbonylhydrazine (0.991 g,
5.5 mmol), mp 64–65 ꢀC (from light petroleum); (Found:
MH+, 249.1236. C13H16N2O3+H requires 249.1239); nmax
(CHCl3)/cmꢁ1 3442, 3031, 2990, 2930, 1703, 1613, 1469,
1456, 1428, 1382, 1359, 1320, 1191, 1120; dH (300 MHz,
CDCl3) 7.39–7.32 (5H, m, ArH), 5.21 (2H, s, CH2), 3.35
(3H, s, NMe), 2.44 (3H, s, Me), 1.95 (3H, s, Me); dC
(75 MHz, CDCl3) 199.2 (C), 164.8 (C), 153.6 (C), 136.3
(C), 129.0 (CH), 128.8 (CH), 128.5 (CH), 68.5 (CH2), 39.3
(Me), 25.6 (Me), 14.6 (Me); m/z (CI) 339 (30%), 249
(MH+, 100), 205 (25), 181 (10), 137 (10), 91 (48).
4.7.14. 1-(Benzyloxycarbonylmethylamino)-3-(tert-bu-
tyldimethylsiloxy)-2-methyl-1-aza-1,3-butadiene 17c.
Following general procedure 4, the title compound
(1.01 g, 93%) was obtained as a pale oil from N-benzyloxy-
4.7.10. 3-(Piperidin-1-ylimino)-butan-2-one. Following
general procedure 3, the title compound (1.02 g, 62%) was
obtained as a pale oil from 1-aminopiperidine (1.10 g,
11.0 mmol); (Found: MH+, 169.1363. C9H16N2O+H
requires 169.1341); nmax (film)/cmꢁ1 2939, 2856, 2822,
1687, 1581, 1443, 1354, 1294, 1261, 1156, 1119, 1103,
1074, 1014; dH (300 MHz, CDCl3) 3.12–3.08 (4H, m,
2ꢃCH2), 2.35 (3H, s, Me), 1.98 (3H, s, Me), 1.74–1.67
(4H, m, 2ꢃCH2), 1.59–1.54 (2H, m, CH2); dC (75 MHz,
CDCl3) 199.7 (C), 152.4 (C), 55.9 (CH2), 25.7 (CH2), 24.9
(Me), 24.4 (CH2), 13.6 (Me); m/z (CI) 197 (8%), 169
(MH+, 100), 84 (15).
carbonyl-N-methyl
butane-2,3-dione
monohydrazone
(0.745 g, 3.0 mmol); (Found: MH+, 363.2097. C19H30N2O3-
Si+H requires 363.2104); nmax (CHCl3)/cmꢁ1 3024, 3016,
2958, 2932, 2887, 2859, 1698, 1595, 1472, 1427, 1389,
1336, 1256, 1228, 1168; dH (300 MHz, CDCl3) 7.35–7.32
(5H, m, ArH), 5.15 (2H, s, CH2), 5.04 (1H, d, J¼1.3 Hz,
C]CH), 4.60 (1H, d, J¼1.3 Hz, C]CH), 3.20 (3H, s,
NMe), 1.93 (3H, s, Me), 0.95 (9H, s, CMe3), 0.16 (6H, s,
SiMe2); dC (75 MHz, CDCl3) 178.0 (C), 163.5 (C), 154.7

5460
M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
(C), 136.8 (C), 128.9 (CH), 128.5 (CH), 128.4 (CH), 98.7
(CH2), 67.9 (CH2), 38.1 (Me), 26.1 (Me), 16.0 (CMe3),
14.5 (Me), ꢁ2.5 (SiMe2); m/z (CI) 453 (8%), 363 (MH+,
25), 339 (8), 311 (10), 283 (80), 271 (22), 249 (12), 221
(20), 193 (57), 181 (25), 149 (27), 137 (18), 91 (100).
over MgSO4 and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography on silica, elut-
ing with ethyl acetate–light petroleum (1:4) to afford the
title compound as yellow crystals (0.076 g, 34%); data
as above.
(d) To a stirred solution of 14a (0.125 g, 0.401 mmol) in
THF (4 mL) was added dropwise TBAF (1.0 M in
THF, 1 mL, 1.00 mmol). Stirring was continued for
2 h, and the reaction was quenched with water
(10 mL) and extracted with ethyl acetate (4ꢃ10 mL).
The combined organics were washed with brine
(10 mL), dried over MgSO4 and concentrated in vacuo.
The crude product was purified by flash chromatography
on silica, eluting with ethyl acetate–light petroleum
(1:1) to afford the title compound as a pale oil
(0.064 g, 71%); data as above.
4.7.15. N-Phthaloyl butane-2,3-dione monohydrazone.
To
a
stirred solution of 2,3-butanedione (8.61 g,
0.100 mol) in chloroform (200 mL) was added N-amino-
phthalimide (17.8 g, 0.110 mol). The reaction mixture was
heated under reflux for 3 days, allowed to cool to room tem-
perature, filtered and concentrated in vacuo to afford the title
compound as a colourless solid (20.1 g, 87%), mp 157–
158 ꢀC (from chloroform), (lit.38 mp 165 ꢀC), which was
used without further purification; dH (300 MHz, CDCl3)
7.95–7.92 (2H, m, ArH), 7.82–7.79 (2H, m, ArH), 2.60
(3H, s, Me), 2.11 (3H, s, Me).
4.7.18. Dimethyl 5-(tert-butyldimethylsiloxy)-6-methyl-
pyridine-2,3-dicarboxylate 14a
4.7.16. 3-(tert-Butyldimethylsiloxy)-2-methyl-1-(phthali-
mido)-1-aza-1,3-butadiene 17d. Following general proce-
dure 4, the title compound (1.38 g, 79%) was obtained as
a colourless solid from N-phthaloyl butane-2,3-dione mono-
hydrazone (1.15 g, 5.0 mmol), mp 106–107 ꢀC (from etha-
nol); (Found: MH+, 345.1632. C18H24N2O3Si+H requires
345.1634); nmax (CHCl3)/cmꢁ1 2955, 2930, 2894, 2857,
1787, 1717, 1618, 1596, 1467, 1373, 1354, 1339, 1311,
1256, 1170, 1115; dH (300 MHz, CDCl3) 7.89–7.86 (2H,
m, ArH), 7.76–7.73 (2H, m, ArH), 5.30 (1H, d, J¼1.3 Hz,
C]CH), 4.75 (1H, d, J¼1.3 Hz, C]CH), 2.07 (3H, s,
Me), 1.00 (9H, s, CMe3), 0.23 (6H, s, SiMe2); dC
(75 MHz, CDCl3) 174.0 (C), 164.3 (C), 153.8 (C), 134.6
(CH), 131.6 (C), 124.0 (CH), 100.3 (CH2), 26.1 (Me), 18.7
(CMe3), 17.5 (Me), ꢁ4.7 (SiMe2); m/z (CI) 373 (10%),
345 (MH+, 95), 287 (50), 200 (32), 148 (100).
(a) Following general procedure 6 from 13a (0.330 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.190 g, 56%) was obtained in 6 h as
a pale oil; (Found: M+, 339.1507. C16H25NO5Si requires
339.1502); nmax (film)/cmꢁ1 2955, 2933, 2888, 2860,
1732, 1588, 1461, 1431, 1406, 1367, 1325, 1258,
1178, 1145, 1055, 1004; dH (300 MHz, CDCl3) 7.35
(1H, s, H-4), 3.95 (3H, s, OMe), 3.90 (3H, s, OMe),
2.52 (3H, s, Me), 1.00 (9H, s, CMe3), 0.25 (6H, s,
SiMe2); dC (75 MHz, CDCl3) 167.1 (C), 166.5 (C),
155.0 (C), 151.8 (C), 142.0 (C), 126.4 (C), 125.0
(CH), 53.4 (Me), 53.3 (Me), 26.2 (Me), 20.5 (Me),
18.6 (CMe3), ꢁ3.9 (SiMe2); m/z (EI) 339 (M+, 12%),
308 (8), 282 (36), 250 (100), 222 (18), 192 (28), 164
(20).
4.7.17. Dimethyl 5-hydroxy-6-methylpyridine-2,3-dicar-
boxylate 9a
(b) Following general procedure 6 from 13a (0.330 g,
1.0 mmol) and DMAD (5, 0.142 g, 1.0 mmol), the title
compound (0.170 g, 50%) was obtained in 8 h as
a pale oil; data as above.
(c) Following general procedure 7 from 13a (0.330 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.190 g, 56%) was obtained in 2 h as
a pale oil; data as above.
(d) Following general procedure 7 from 13a (0.330 g,
1.0 mmol) and DMAD (5, 0.142 g, 1.0 mmol), the title
compound (0.170 g, 50%) was obtained in 3 h as
a pale oil; data as above.
(e) A solution of 1-azadiene 13a (0.330 g, 1.0 mmol) and
DMAD (5, 0.284 g, 2.0 mmol) in toluene (2 mL) in
a sealed tube was heated to 150 ꢀC for 6 h. The resulting
mixture was concentrated in vacuo and the crude prod-
uct was purified by flash chromatography on silica, elut-
ing with ethyl acetate–light petroleum (1:19) to afford
the title compound (0.194 g, 57%) as a pale oil; data
as above.
(a) Following general procedure 5 from 4a (0.466 g,
1.9 mmol) and DMAD (5, 0.270 g, 1.9 mmol) the title
compound (0.162 g, 38%) was obtained after 4 days in
toluene as yellow crystals, mp 163–166 ꢀC (from ethyl
acetate–light petroleum), (lit.17 mp 157–159 ꢀC); dH
(300 MHz, CDCl3) 9.50 (1H, br s, OH), 7.41 (1H, s,
H-4), 3.90 (6H, s, 2ꢃOMe), 2.54 (3H, s, Me); dC
(75 MHz, CDCl3) 166.9 (C), 166.4 (C), 153.2 (C),
150.5 (C), 138.7 (C), 127.6 (C), 121.3 (CH), 53.1
(2ꢃMe), 18.8 (Me).
(b) Following general procedure 5 from 3-(trimethyl-
siloxy)-1-(dimethylamino)-2-methyl-1-aza-1,3-butadiene
(0.721 g, 3.6 mmol) and DMAD (5, 0.512 g, 3.6 mmol)
the title compound (0.246 g, 30%) was obtained after 5
days in toluene as yellow crystals; data as above.
(c) A solution of the 1-aza-1,3-butadiene 15 (0.242 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol) in toluene
(2 mL) in a sealed microwave tube (10 mL capacity)
was irradiated at 300 W with simultaneous cooling
and held at 150 ꢀC for 2 h. The resulting mixture was
concentrated in vacuo. The residue was taken up in
methanol (1 mL), 2 M HCl (1 mL) was added and the
mixture was stirred for 5 min. The mixture was then neu-
tralised with saturated NaHCO3, extracted with ethyl ac-
etate (3ꢃ15 mL) and the combined organics were dried
(f) Following general procedure 6 from 17a (0.242 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.176 g, 52%) was obtained in 2 h as
a pale oil; data as above.
(g) Following general procedure 7 from 17a (0.242 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.150 g, 44%) was obtained in 45 min as
a pale oil; data as above.

M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
5461
(h) Following general procedure 6 from 17b (0.283 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.160 g, 47%) was obtained in 2 h as
a pale oil; data as above.
(i) Following general procedure 6 from 17c (0.363 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.157 g, 46%) was obtained in 4 h as
a pale oil; data as above.
(j) Following general procedure 7 from 17d (0.344 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.197 g, 58%) was obtained in 3 h as
a pale oil; data as above.
C, 59.1; H, 4.38; N, 4.06%); (Found: M+, 345.0850.
C17H15NO7 requires 345.0849); nmax (Nujol)/cmꢁ1 3500–
3100, 1735, 1725, 1685, 1560, 1460, 1430, 1345, 1315,
1265, 1200, 1150, 1130; dH (300 MHz, CDCl3) 11.00 (1H,
s, OH), 7.66 (1H, s, H-4), 7.49–7.30 (5H, m, ArH), 5.50
(2H, s, CH2), 3.93 (3H, s, OMe), 3.92 (3H, s, OMe); dC
(75 MHz, CDCl3) 168.3 (C), 165.2 (C), 165.1 (C), 159.4
(C), 140.4 (C), 134.6 (C), 133.5 (C), 130.8 (C), 128.8
(CH), 128.7 (CH), 128.7 (CH), 127.0 (CH), 68.4 (CH2),
53.2 (Me), 53.1 (Me); m/z (EI) 345 (M+, 3%), 314 (17),
239 (70), 211 (89), 179 (3), 91 (100).
(k) Following general procedure 7 from 17d (0.344 g,
1.0 mmol) and DMAD (5, 0.142 g, 1.0 mmol), the title
compound (0.183 g, 54%) was obtained in 4 h as
a pale oil; data as above.
(l) A solution of 1-azadiene 17a (0.242 g, 1.0 mmol) and
DMAD (5, 0.284 g, 2.0 mmol) in toluene (2 mL) in
a sealed tube was heated to 150 ꢀC for 2 h. The resulting
mixture was concentrated in vacuo and the crude prod-
uct was purified by flash chromatography on silica, elut-
ing with ethyl acetate–light petroleum (1:19) to afford
the title compound (0.157 g, 46%) as a pale oil; data
as above.
4.7.22. 2,3-Di-tert-butyl-6-methyl 5-hydroxypyridine-
2,3,6-tricarboxylate 10. Following general procedure 5
from 4b (0.811 g, 2.8 mmol) and DBAD (6, 0.634 g,
2.8 mmol) the title compound (0.320 g, 32%) was obtained
after 7 days in toluene as yellow crystals, mp 119–122 ꢀC
(from ethanol); (Found: C, 57.7; H, 6.51; N, 3.87.
C17H23NO7 requires C, 57.8; H, 6.56; N, 3.96%); (Found:
M+, 353.1472. C17H23NO7 requires 353.1475); nmax (Nu-
jol)/cmꢁ1 3230, 1735, 1685, 1560, 1455, 1370, 1315,
1200, 1145, 1120; dH (400 MHz, CDCl3) 10.92 (1H, s,
OH), 7.60 (1H, s, H-4), 4.05 (3H, s, OMe), 1.62 (9H, s,
CMe3), 1.60 (9H, s, CMe3); dC (100 MHz, CDCl3) 168.9
(C), 164.0 (C), 163.7 (C), 158.8 (C), 142.5 (C), 134.6 (C),
129.9 (C), 126.9 (H-4), 83.4 (CMe3), 83.1 (CMe3), 53.3
(Me), 27.9 (2ꢃCMe3); m/z (EI) 353 (M+, 0.6%), 297 (1),
253 (5), 252 (5), 242 (65), 224 (56), 198 (44), 197 (21),
192 (13), 179 (10), 167 (21), 139 (34), 57 (100).
4.7.19. Trimethyl 5-hydroxypyridine-2,3,6-tricarboxy-
late 9b. Following general procedure 5 from 4b (0.839 g,
2.9 mmol) and DMAD (5, 0.412 g, 2.9 mmol) the title com-
pound (0.327 g, 42%) was obtained after 4 days in benzene
as yellow crystals, mp 121–124 ꢀC (from ethanol), (lit.17 mp
118–119 ꢀC); dH (400 MHz, CDCl3) 11.05 (1H, s, OH), 7.66
(1H, s, H-4), 4.06 (3H, s, OMe), 3.96 (3H, s, OMe), 3.95 (3H,
s, OMe); dC (75 MHz, CDCl3) 168.8 (C), 165.3 (C), 159.4
(C), 159.4 (C), 139.8 (C), 134.0 (C), 127.0 (CH), 54.7
(Me), 53.3 (Me), 53.2 (Me).
4.7.23. Trimethyl 5-(tert-butyldimethylsiloxy)pyridine-
2,3,6-tricarboxylate 14b
(a) Following general procedure 6 from 13b (0.374 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.121 g, 32%) was obtained in 10 h as
a pale oil; (Found: M+, 384.1473. C17H25NO7Si+H re-
quires 384.1478); nmax (CHCl3)/cmꢁ1 2955, 2934,
2888, 2862, 2254, 1742, 1589, 1555, 1430, 1409,
1363, 1336, 1253, 1215, 1170, 1148, 1119, 1047; dH
(300 MHz, CDCl3) 7.48 (1H, s, H-4), 3.92 (3H, s,
OMe), 3.91 (3H, s, OMe), 3.90 (3H, s, OMe), 0.96
(9H, s, CMe3), 0.25 (6H, s, SiMe2); dC (75 MHz,
CDCl3) 165.9 (C), 165.7 (C), 164.7 (C), 152.7 (C),
144.0 (C), 141.4 (C), 131.3 (C), 128.7 (CH), 53.6
(Me), 53.5 (Me), 53.2 (Me), 25.7 (Me), 18.6 (CMe3),
ꢁ3.8 (SiMe2); m/z (CI) 384 (MH+, 6%), 270 (100),
238 (23).
(b) Following general procedure 7 from 13b (0.374 g,
1.0 mmol) and DMAD (5, 0.284 g, 2.0 mmol), the title
compound (0.119 g, 31%) was obtained in 6 h as
a pale oil; data as above.
(c) Following general procedure 7 from 13b (0.374 g,
1.0 mmol) and DMAD (5, 0.142 g, 1.0 mmol), the title
compound (0.171 g, 45%) was obtained in 8 h as
a pale oil; data as above.
4.7.20. 6-tert-Butyl-2,3-dimethyl 5-hydroxypyridine-
2,3,6-tricarboxylate 9c. Following general procedure 5
from 4c (0.431 g, 1.3 mmol) and DMAD (5, 0.185 g,
1.3 mmol) the title compound (0.157 g, 39%) was obtained
after 14 days in toluene as yellow crystals, mp 64–70 ꢀC
(from ether); (Found: C, 54.0; H, 5.47; N, 4.50.
C14H17NO7 requires C, 54.0; H, 5.50; N, 5.50%); (Found:
M+, 311.1013. C14H17NO7 requires 311.1005); nmax (film)/
cmꢁ1 3300–2800, 1740, 1675, 1570, 1430, 1370, 1320,
1265, 1220, 1150, 1125, 1050, 970; dH (400 MHz, CDCl3)
11.34 (1H, s, OH), 7.62 (1H, s, H-4), 3.94 (3H, s, OMe),
3.92 (3H, s, OMe), 1.66 (9H, s, CMe3); dC (100 MHz,
CDCl3) 168.0 (C), 165.5 (C), 165.3 (C), 159.4 (C), 139.7
(C), 133.2 (C), 132.0 (C), 126.7 (CH), 85.6 (CMe3), 53.1
(Me), 52.9 (Me), 28.0 (CMe3); m/z (EI) 311 (M+, 2%), 296
(5), 280 (10), 257 (19), 256 (74), 255 (35), 238 (34), 225
(22), 224 (81), 211 (10), 210 (63), 206 (48), 181 (14), 180
(26), 179 (85), 178 (29), 167 (17), 150 (15), 139 (32), 123
(18), 122 (10), 121 (36), 95 (11), 94 (17), 93 (22), 69 (16),
59 (39), 58 (14), 57 (100) 56 (48).
4.7.21. 6-Benzyl-2,3-dimethyl 5-hydroxypyridine-2,3,6-
tricarboxylate 9d. Following general procedure 5 from 4d
(0.585 g, 1.6 mmol) and DMAD (5, 0.227 g, 1.6 mmol) the
title compound (0.267 g, 48%) was obtained after 6 days
in toluene as yellow crystals, mp 116–118 ꢀC (from etha-
nol); (Found: C, 58.9; H, 4.21; N, 3.95. C17H15NO7 requires
4.7.24. 2-Benzyl-6-methyl 3-hydroxypyridine-2,6-dicar-
boxylate 11.
(0.621 g, 1.7 mmol) and methyl propiolate (7, 0.294 g,
3.5 mmol) in toluene (2 mL) in a sealed tube was heated to
120 ꢀC for 4 days. The resulting mixture was concentrated
in vacuo and the crude product was purified by flash
A solution of 1-aza-1,3-butadiene 4d

5462
M. D. Fletcher et al. / Tetrahedron 62 (2006) 5454–5463
chromatography on silica, eluting with methanol–chloro-
form (0.5:99.5–2:98) to afford the title compound (0.103 g,
21%) as yellow crystals, mp 102–106 ꢀC (from ethanol);
(Found: M+, 287.0788. C15H13NO5 requires 287.0794);
nmax (Nujol)/cmꢁ1 1725, 1665, 1595, 1580, 1430, 1425,
1350, 1310, 1220, 1180, 1135, 1095; dH (400 MHz,
CDCl3) 11.10 (1H, s, OH), 8.22 (1H, d, J¼8.8 Hz, ArH),
7.52–7.47 (2H, m, ArH), 7.44 (1H, d, J¼8.8 Hz, ArH),
7.41–7.31 (3H, m, ArH), 5.52 (2H, s, CH2), 3.96 (3H, s,
OMe); dC (100 MHz, CDCl3) 169.0 (C), 164.6 (C), 161.0
(C), 139.8 (C), 134.8 (C), 131.0 (CH), 130.0 (C), 128.8
(CH), 128.7 (CH), 128.6 (CH), 126.7 (CH), 68.2 (CH2),
52.8 (Me); m/z (EI) 287 (M+, 0.4%), 256 (1), 181 (22),
153 (26), 92 (19), 91 (100), 65 (20), 57 (29), 55 (18).
(9H, s, CMe3), 0.25 (6H, s, SiMe2); dC (75 MHz, CDCl3)
199.9 (C), 153.8 (C), 150.7 (C), 146.6 (C), 124.7 (CH),
121.5 (CH), 26.0 (Me), 20.5 (Me), 18.6 (CMe3), ꢁ3.5
(SiMe2); m/z (CI) 266 (MH+, 100%), 152 (5).
Acknowledgements
We thank the EPSRC for funding, GlaxoSmithKline for
a CASE award (T.E.H) and the EPSRC Mass Spectrometry
Centre at Swansea for mass spectra.
References and notes
4.7.25. Methyl 6-acetyl-3-hydroxypyridine-2-carboxyl-
ate 12. A solution 1-aza-1,3-butadiene 4b (0.345 g,
1.19 mmol) and 3-butyn-2-one (8, 0.406 g, 5.96 mmol) in
toluene (5 mL) in a sealed tube was heated to 110 ꢀC for
20 h. The resulting mixture was concentrated in vacuo and
the crude product was purified by flash chromatography on
silica, eluting with ethyl acetate–light petroleum (1:3) to
afford the title compound (0.090 g, 39%) as yellow crystals,
mp 125–127 ꢀC (from ethyl acetate–light petroleum);
(Found: C, 55.1; H, 4.65; N, 7.18. C9H9NO4 requires C,
55.4; H, 4.45; N, 7.04%); (Found: M+, 195.0528.
C9H9NO4 requires 195.0532); nmax (Nujol)/cmꢁ1 3120,
1700, 1685, 1655, 1575, 1560, 1540, 1290, 1275, 1210,
1175, 1130, 1105, 1090; dH (300 MHz, CDCl3) 11.08 (1H,
s, OH), 8.15 (1H, d, J¼8.8 Hz, ArH), 7.40 (1H, d,
J¼8.8 Hz, ArH), 4.05 (3H, s, OMe), 2.67 (3H, s, COMe);
dC (100 MHz, CDCl3) 198.2 (C), 169.6 (C), 161.3 (C),
145.9 (C), 128.6 (C), 127.9 (CH), 126.6 (CH), 53.3 (Me),
25.2 (Me); m/z (EI) 195 (M+, 100%), 180 (16), 167 (13),
153 (24), 152 (50), 137 (56), 136 (17), 135 (28), 122 (23),
121 (68), 120 (22), 107 (31), 94 (17), 93 (19), 64 (15), 59
(19), 53 (15).
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idine-6-carboxylate 18. Following general procedure 7
from 17a (0.242 g, 1.0 mmol) and methyl propiolate (7,
0.168 g, 2.0 mmol), the title compound (0.082 g, 29%) was
obtained in 6 h as a pale oil; (Found: M+, 282.1526.
C14H23NO3Si requires 282.1525); nmax (film)/cmꢁ1 2956,
2934, 2887, 2861, 2254, 2235, 1719, 1574, 1463, 1408,
1392, 1364, 1325, 1258, 1199, 1120, 1007; dH (300 MHz,
CDCl3) 7.88 (1H, d, J¼8.3 Hz, ArH), 7.06 (1H, d,
J¼8.3 Hz, ArH), 3.92 (3H, s, OMe), 3.51 (3H, s, Me),
0.98 (9H, s, CMe3), 0.22 (6H, s, SiMe2); dC (75 MHz,
CDCl3) 168.3 (C), 156.0 (C), 154.4 (C), 142.1 (C), 127.2
(CH), 127.0 (CH), 55.5 (Me), 28.2 (Me), 22.8 (Me), 20.8
(CMe3), ꢁ1.3 (SiMe2); m/z (CI) 282 (M+, 100%).
4.7.27. 6-Acetyl-3-(tert-butyldimethylsiloxy)-2-methyl-
pyridine 19. Following general procedure 7 from 17a
(0.242 g, 1.0 mmol) and 3-butyn-2-one (8, 0.136 g,
2.0 mmol), the title compound (0.073 g, 28%) was obtained
in 6 h as a pale oil; (Found: M+, 339.1507. C14H23NO3Si
requires 339.1502); nmax (CHCl3)/cmꢁ1 2933, 2959, 2887,
2861, 2252, 1684, 1643, 1596, 1569, 1508, 1460, 1392,
1359, 1309, 1256, 1211, 1181, 1117, 1006; dH (300 MHz,
CDCl3) 7.83 (1H, d, J¼8.3 Hz, ArH), 7.07 (1H, d,
J¼8.3 Hz, ArH), 2.66 (3H, s, Me), 2.49 (3H, s, Me), 1.02
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